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Research shows variable clinical response to pembrolizumab in patients with uterine cancer
New research from Yale Cancer Center shows for the first time ever a differential clinical response to pembrolizumab in patients with Lynch-like (mutant) vs. methylated microsatellite instability-high (MSI-H), expanding our understanding of the proportion of patients who benefit from immune checkpoint blockade. The results were published today in the journal Cancer Discovery. Defects in DNA mismatch repair (MMR) genes are common in tumors and are usually caused by an inherited defect in the function of one of the MMR genes. The main feature of these tumors is that they are associated with genome-wide instability and the progressive accumulation of mutations, particularly in regions with simple repetitive DNA sequences that...
Research shows variable clinical response to pembrolizumab in patients with uterine cancer
New research from Yale Cancer Center shows for the first time ever a differential clinical response to pembrolizumab in patients with Lynch-like (mutant) vs. methylated microsatellite instability-high (MSI-H), expanding our understanding of the proportion of patients who benefit from immune checkpoint blockade.
The results were published today in the journal Cancer Discovery.
Defects in DNA mismatch repair (MMR) genes are common in tumors and are usually caused by an inherited defect in the function of one of the MMR genes. The key feature of these tumors is that they are associated with genome-wide instability and the progressive accumulation of mutations, particularly in regions with simple repetitive DNA sequences known as microsatellites, resulting in high microsatellite instability (MSI) tumors (MSI-H). Cancers deficient in MMR gene function (dMMR) are widespread in many solid tumors and account for up to 30% of all uterine tumors, 20% of gastric cancer and 15% of colon cancer, among others.
Due to the high number of mutations, MSI-H tumors are considered highly immunogenic and therefore respond very well (~50% response rate in terms of complete or partial response) to immunotherapy treatment in the form of immune checkpoint blockade antibodies such as pembrolizumab. However, the question remained why only 50% of patients with MSI-H/dMMR features responded and not 100%.”
Dr. Eric Song, resident in immunobiology and co-author of the study
A phase 2 clinical trial of the PD-1 inhibitor pembrolizumab provided a partial answer to this question. The study was conducted in 24 patients with mismatch repair-deficient (MMRd) endometrial cancer and found that responses to pembrolizumab were stronger and significantly longer lasting in Lynch-like (mutant) patients than in patients with MSI-H methylated endometrial cancer.
“These results highlighted for the first time the heterogeneity and prognostic significance of patients with endometrial cancer with Lynch-like versus sporadic/methylated MSI-H in terms of overall response, progression-free survival and overall survival when treated with pembrolizumab,” said Dr. Alessandro Santin, professor of obstetrics, gynecology and reproductive sciences and senior author of the study. He is also co-head of the Gynecological Oncology section.
“Endometrial cancer is the most common gynecologic cancer affecting women in developed countries, due in part to increasing obesity and our aging population,” said lead author Ryan Chow, an MD/PhD student at Yale. "We believe that a fruitful area for future research will be to examine the underlying mechanisms that drive the two different types of anti-tumor immunity in patients. These data may reveal whether the distinguishing features of the circulating immune response that we have identified here are similarly observed in tumor-infiltrating immune cells."
The study was funded in part by grants from the National Institutes of Health, Gilead Sciences, Merck & Co. Inc. and the Stand Up to Cancer Foundation.
Other Yale authors include Tai Michaels, Stefania Bellone, Tobias MP Hartwich, Elena Bonazzoli and Akiko Iwasaki.
Source:
Reference:
Chow, R.D., et al. (2022) Different mechanisms of mismatch repair deficiency describe two modes of response to PD-1 immunotherapy in endometrial cancer. Cancer discovery. doi.org/10.1158/2159-8290.CD-22-0686.
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